Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified. TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells. TPH catalyzes the hydroxylation of tryptophan in the biosynthesis of 5-HT. Thus, the pharmacological effects of 5-HT can be modulated by agents affecting TPH.
TPH1 inhibitors are known in the art. Spirocyclic compounds disclosed in U.S. Ser. No. 14/477,948, filed Sep. 5, 2014, can inhibit TPH1 and were found to reduce peripheral serotonin levels in animal models. The preparation of these compounds can include the coupling of an alcohol with a chloro-substituted heteroaromatic compound in the presence of base to yield an ether intermediate that can be used to make the final TPH1 inhibitor product. A particular chiral alcohol useful in the synthesis of TPH1 inhibitors is (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (see Formula A below). According to U.S. Ser. No. 14/477,948, this chiral alcohol is made by the coupling of phenyl boronic acid with (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol. Alternative processes for the preparation of the compound of Formula A are provided herein.